One-pot tandem Hurtley-retro-Claisen-cyclisation reactions in the synthesis of 3-substituted analogues of 5-aminoisoquinolin-1-one (5-AIQ), a water-soluble inhibitor of PARPs

Bioorg Med Chem. 2013 Sep 1;21(17):5218-27. doi: 10.1016/j.bmc.2013.06.031. Epub 2013 Jun 22.

Abstract

Poly(ADP-ribose)polymerase-1 (PARP-1) is an important target for drug design for several therapeutic applications. 5-Aminoisoquinolin-1-one (5-AIQ) is a highly water-soluble lead compound; synthetic routes to 3-substituted analogues were explored. Tandem Hurtley coupling of β-diketones with 2-bromo-3-nitrobenzoic acid, retro-Claisen acyl cleavage and cyclisation gave the corresponding 3-substituted 5-nitroisocoumarins. Treatment with ammonia at high temperature and reduction with tin(II) chloride gave eleven target 3-substituted 5-AIQs, which were all soluble in water (>1% w/v) as their HCl salts. Most were more potent than 5-AIQ as inhibitors of PARP-1 and of PARP-2 in vitro, the most active being 5-amino-3-methylisoquinolin-1-one (PARP-1: IC50=0.23μM vs IC50=1.6μM for 5-AIQ). Some rationalisation of the SAR was achieved through molecular modelling.

Keywords: Hurtley reaction; Isocoumarin; Isoquinolin-1-one; PARP-1; Tandem.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Chickens
  • Cyclization
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Hydrogen Bonding
  • Isoquinolines / chemical synthesis
  • Isoquinolines / chemistry*
  • Molecular Docking Simulation
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Water / chemistry

Substances

  • Enzyme Inhibitors
  • Isoquinolines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Water
  • Poly(ADP-ribose) Polymerases